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WO1999065942A1 - Analogues de somatostatine cycliques - Google Patents

Analogues de somatostatine cycliques Download PDF

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Publication number
WO1999065942A1
WO1999065942A1 PCT/US1999/013304 US9913304W WO9965942A1 WO 1999065942 A1 WO1999065942 A1 WO 1999065942A1 US 9913304 W US9913304 W US 9913304W WO 9965942 A1 WO9965942 A1 WO 9965942A1
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WIPO (PCT)
Prior art keywords
trp
phe
lys
imidazole
cyclo
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PCT/US1999/013304
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English (en)
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WO1999065942A8 (fr
Inventor
Thomas D. Gordon
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Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S.
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Application filed by Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. filed Critical Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S.
Priority to US09/719,784 priority Critical patent/US6602849B1/en
Priority to JP2000554767A priority patent/JP2002518409A/ja
Priority to CA002335184A priority patent/CA2335184A1/fr
Priority to HU0102902A priority patent/HUP0102902A3/hu
Priority to EP99931793A priority patent/EP1086131A1/fr
Priority to PL99345037A priority patent/PL345037A1/xx
Priority to AU48223/99A priority patent/AU745493B2/en
Publication of WO1999065942A1 publication Critical patent/WO1999065942A1/fr
Publication of WO1999065942A8 publication Critical patent/WO1999065942A8/fr
Priority to NO20006320A priority patent/NO20006320L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/655—Somatostatins
    • C07K14/6555—Somatostatins at least 1 amino acid in D-form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention is directed to cyclic derivatives containing an imidazole cis amide bond mimetic which bind selectively to somatostatin receptor subtypes. This invention is also directed to methods for making the compounds of the instant invention.
  • Somatostatin is a cyclic tetradecapeptide hormone containing a disulfide bridge between position 3 and position 14 and has the properties of inhibiting the release of growth hormone (GH) and thyroid-stimulating hormone (TSH), inhibiting the release of insulin and glucagon, and reducing gastric secretion. Metabolism of somatostatin by aminopeptidases and carboxypeptidases leads to a short duration of action. Somatostatin binds to five distinct receptor (SSTR) subtypes with relatively high affinity for each subtype. The smaller, more rigid analogs of the present invention exhibit high selectivity for several of the receptor subtypes.
  • Binding to the different types of somatostatin subtypes have been associated with the treatment of the following conditions and/or diseases. Activation of types 2 and 5 have been associated with growth hormone suppression and more particularly GH secreting adenomas (Acromegaly) and TSH secreting adenomas. Activation of type 2 but not type 5 has been associated with treating prolactin secreting adenomas.
  • somatostatin subtypes are restenosis, inhibition of insulin and/or glucagon and more particularly diabetes mellitus, hyperiipidemia, insulin insensitivity, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon and Nephropathy; inhibition of gastric acid secretion and more particularly peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, irritable bowel syndrome, Dumping syndrome, watery diarrhea syndrome, AIDS related diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis and gastrointestinal hormone secreting tumors; treatment of cancer such as hepatoma; inhibition of angiogenesis, treatment of inflammatory disorders such as arthritis; chronic allograft rejection; angioplasty; preventing graft vessel and gastrointestinal bleeding.
  • Somatostatin agonists can also be used for decreasing body weight in a patient.
  • Somatostatin agonists have also been disclosed to be useful for inhibiting the proliferation of helicobacter pylori.
  • the present invention provides a compound of the formula (I),
  • Y and Z for each occurrence are each independently a D- or L-natural or unnatural ⁇ -amino acid; n for each occurrence is independently 0 to 50, provided that both n cannot be 0 at the same time; m is 0 or an integer from 1 to 10; a is H or R 1 ; b is OH, -OR 1 or -NR 9 R 9 ; or a is taken together with b to form an amide bond;
  • R 1 is independently H, (C r C 4 )alkyl or aryl-(C 1 -C 4 )alkyl;
  • R 2 is H or an optionally substituted moiety selected from the group consisting of (C C 4 )alkyl, phenyl, phenyl-(C 1 -C 4 )alkyl and heterocyclyl-(C 1 -C 4 )alkyl, where the optionally substituted moiety is optionally substituted by one or more substituents each independently selected from the group consisting of (C 1 -C 4 )alkyl, (C 3 -
  • R 3 and R 4 are each independently H, halo or an optionally substituted moiety selected from the group consisting of (C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, aryl and aryl-
  • (C 1 -C 4 )alkyl where the optionally substituted moiety is optionally substituted by one or more substituents selected from the group consisting of OH, (C 1 -C 4 )alkyl, (C,- C 4 )alkoxy, aryloxy, aryl-(C 1 -C 4 )alkoxy, -NR 9 R 9 , COOH, -CONR 9 R 9 and halo, or R 3 and R 4 are taken together with the carbons to which they are attached to form optionally substituted aryl, where the aryl is optionally substituted by one or more substituents each independently selected from the group consisting of OH, (C,--
  • R 5 for each occurrence is independently H, or an optionally substituted moiety selected from the group consisting of (C C 4 )aikyl and aryl-(C 1 -C 4 )alkyl, where the optionally substituted moiety is optionally substituted by one or more substituents each independently selected from the group consisting of (C 1 -C 4 )alkyl, OH, (C,- C 4 )alkoxy, aryloxy, N0 2) aryl-(C r C 4 )alkoxy, -NR 9 R 9 , COOH, -CONR 9 R 9 and halo,
  • R 6 for each occurrence is independently selected from the group consisting of
  • R 7 is H when q is 3 or, R 7 for each occurrence is independently selected from the group consisting of (C 1 -C 4 )alkyl, aryl or aryl-(C r C 4 )alkyl when q is 0, 1 or 2, and
  • R 9 for each occurrence is independently selected from the group consisting of
  • a preferred compound of formula (I) is the compound H-Trp-D-Trp-Lys-Abu-
  • Y and Z for each occurrence are each independently a D- or L-natural or unnatural ⁇ -amino acid; m is 0 or an integer from 1 to 10, n for each occurrence is independently 0 to 6;
  • R 1 for each occurrence is independently H, (C 1 -C 4 )alkyl or aryl-(C 1 -C 4 )alkyl;
  • R 2 is H or an optionally substituted moiety selected from the group consisting of (C,- C 4 )alkyl, phenyl, phenyl-(C 1 -C 4 )alkyl and heterocyclyl-(C 1 -C 4 )alkyl, where the optionally substituted moiety is optionally substituted by one or more substituents each independently selected from the group consisting of (C 1 -C 4 )alkyl, cycloalkyl, -O-
  • R 3 and R 4 are each independently H, halo or an optionally substituted moiety selected from the group consisting of (C 1 -C 4 )alkyl, cycloalkyl, aryl and ary C,- C 4 )alkyl; where the optionally substituted moiety is optionally substituted by one or more substituents selected from the group consisting of OH, (C 1 -C 4 )alkyl, (C r C 4 )alkoxy, aryloxy, aryl-(C r C 4 )alkoxy, -NR 9 R 9 , COOH, -CONR 9 R 9 and halo; or R 3 and R 4 are taken together with the carbons to which they are attached to form optionally substituted aryl, where the aryl is optionally substituted by one or more substituents each independently selected from the group consisting of OH, (C r C 4 )alkyl, (C 1 -C 4 )alkoxy, aryloxy, aryHC
  • R 6 for each occurrence is independently selected from the group consisting of
  • R 7 is H when q is 3, or R 7 for each occurrence is independently selected from the group consisting of (C 1 -C 4 )alkyl, aryl or aryl-(C 1 -C 4 )alkyl when q is 0, 1 or 2; and
  • R 9 for each occurrence is independently selected from the group consisting of
  • X 1 is a natural or unnatural D- or L- ⁇ -amino acid, where when X 1 is Phe, Nal, Trp,
  • Tyr, Pal or His the aromatic ring thereof is optionally substituted on carbon or nitrogen by R ⁇ or when X 1 is Ser or Thr, the side chain oxygen is optionally substituted by one or more R 1 ;
  • X 2 is D- or L-Trp, N-methyl-D-Trp or N-methyl-L-Trp;
  • X 3 is Lys, ⁇ -N-methyl-Lys or ⁇ -N-(C r C 4 )alkyl-Lys or ⁇ -N-[aryl-(C r C 4 )alkyl]-Lys;
  • X 4 is a natural or unnatural D- or L- ⁇ -amino acid where when X 4 is Phe, Nal, Trp, Tyr or His, the aromatic ring thereof is optionally substituted on carbon or nitrogen by R 8 or when X 4 is Ser, Tyr or Thr, the side chain oxygen may be substituted with one or more R 1 .
  • bonds between X 1 , X 2 , X 3 and X 4 are amide bonds as is the bond between X 1 and Z, and the bond between X 4 and Y.
  • a preferred group of compounds of formula (II), designated group A, is wherein, each n is 2; m is 0 or 1 to 5;
  • R 1 for each occurrence is independently H, methyl or aryl-(C 1 -C 4 )alkyl;
  • R 2 is an optionally substituted moiety selected from the group consisting phenyl-(C r )
  • R 3 and R 4 are each independently H, halo or an optionally substituted moiety selected from the group consisting of (C 1 -C 4 )alkyl and aryl; where the optionally substituted moiety is optionally substituted by a substituent selected from the group consisting of OH, (C C 4 )alkoxy, aryloxy and halo.
  • a preferred group of the group A compounds, designated group B, is wherein
  • X 1 is Phe, Nal, Trp, Tyr, Pal or His, wherein the aromatic ring thereof is optionally substituted on carbon or nitrogen by R 6 ; and X 4 is Val, Abu, Ser, Thr, Nal, Trp, Tyr or His, wherein the aromatic ring of Nal, Trp,
  • Tyr and His is optionally substituted on carbon and/or nitrogen by R 8 or when X 4 is
  • a preferred group of the group B compounds, designated group C, is wherein
  • X 1 is Phe, Trp or Tyr wherein the aromatic ring thereof is optionally substituted on carbon or nitrogen by R 6 ;
  • X 2 is D-Trp or N-methyl-D-Trp
  • X 3 is Lys or ⁇ -N-methyl-Lys
  • X 4 is Val, Thr, Abu, Nal or Tyr, wherein the side chain oxygen of the hydroxy group of
  • Thr and Tyr is optionally substituted by R 1 ;
  • R 1 for each occurrence is independently H, methyl or benzyl;
  • R 2 is an optionally substituted moiety selected from the group consisting phenylmethyl and heterocyclyl-methyl, where the optionally substituted moiety is substituted by a substituent selected from the group consisting of (C 1 -C 4 )alkyl and -
  • R 3 is (C 1 -C 4 )alkyl or optionally substituted aryl; where the optionally substituted aryl is substituted by a substituent selected from the group consisting of OH, (d-
  • R 4 is H
  • R 6 for each occurrence is independently selected from the group consisting of H and aryl-(C 1 -C 4 )alkoxy.
  • a preferred group of the group C compounds, designated group D, is wherein
  • X 1 is Phe, Trp, Tyr or Tyr(OBzl);
  • X 4 is Val, Thr, Abu, Nal, or Tyr, wherein the hydroxy group of Thr and Tyr is optionally substituted benzyl;
  • m is O, 2 or 4;
  • R 2 is an optionally substituted moiety selected from the group consisting of phenylmethyl or 3-indolylmethyl where the optionally substituted moiety is optionally substituted by -O-R 6 ;
  • R 3 is 1 ,1-dimethylethyl or optionally substituted aryl; where the optionally substituted aryl is optionally substituted by a moiety selected from the group consisting of OH, (C 1 -C 4 )alkoxy and halo.
  • a preferred group of the group D compounds, designated group E, is wherein
  • R 2 is phenylmethyl
  • R 3 is 1 ,1-dimethylethyl or optionally substituted phenyl, where the optionally substituted phenyl is optionally substituted by OH or OCH 3 ; and R 6 for each occurrence is independently selected from the group consisting of H or benzylmethoxy.
  • a preferred group of the group E compounds, designated group F, is cyclo [Tyr-D-Trp-Lys-Val-Phe ⁇ (4-(3-methoxyphenyl)imidazole)-Gly], cyclo [Tyr(OBzl)-D-Trp-Lys-Val-Phe ⁇ (4-(3-methoxyphenyl)imidazole)-Gly], cyclo [Trp-D-Trp-Lys-Val-Phe ⁇ (4-(3-methoxyphenyl)imidazole)-Gly], cyclo [Trp-D-Trp-Lys-Val-Phe ⁇ (4-(3-hydroxyphenyl)imidazole)-Gly], cyclo [Trp-D-Trp-Lys-Thr(OBzl)-Phe ⁇ (4-(3-methoxyphenyl)imidazole)-Gly], cyclo [Trp
  • a preferred group of the group F compounds, designated group G is cyclo [Tyr-D-Trp-Lys-Val-Phe ⁇ (4-(3-methoxyphenyl)imidazole)-Gly], cyclo [Tyr(OBzl)-D-Trp-Lys-Val-Phe ⁇ (4-(3-methoxyphenyl)imidazole)-Glyj, cyclo [Trp-D-Trp-Lys-Val-Phe ⁇ (4-(3-methoxyphenyl)imidazole)-Gly], cyclo [Trp-D-Trp-Lys-Val-Phe ⁇ (4-(3-hydroxyphenyl)imidazole)-Gly], cyclo [Trp-D-Trp-Lys-Thr(OBzl)-Phe ⁇ (4-(3-methoxyphenyl)imidazole)-Gly], cyclo [Trp
  • a preferred group of the group G compounds, designated group H, is cyclo [Tyr-D-Trp-Lys-Val-Phe ⁇ (4-(3-methoxyphenyl)imidazole)-Gly], cyclo [Trp-D-Trp-Lys-Val-Phe ⁇ (4-(3-methoxyphenyl)imidazole)-Gly], cyclo [Trp-D-Trp-Lys-Val-Phe ⁇ (4-(3-hydroxyphenyl)imidazole)-Glyj, cyclo [Trp-D-Trp-Lys-Thr-Phe ⁇ (4-(3-hydroxyphenyl)imidazole)-Gly], cyclo [Trp-D-Trp-Lys-Abu-Phe ⁇ (4-(3-methoxyphenyl)imidazole)-Gly], cyclo [Phe-D-Trp-Lys-
  • a preferred group of the group H compounds, designated group I is cyclo [Tyr-D-Trp-Lys-Val-Phe ⁇ (4-(3-methoxyphenyl)imidazole)-Gly], cyclo [Trp-D-Trp-Lys-Val-Phe ⁇ (4-(3-hydroxyphenyl)imidazole)-Gly], cyclo [Trp-D-Trp-Lys-Thr-Phe ⁇ (4-(3-hydroxyphenyl)imidazole)-Gly] and cyclo [Tyr-D-Trp-Lys-Val-Phe ⁇ (4-(3-hydroxyphenyl)imidazole-Gly].
  • group J Another preferred group of the group F compounds, designated group J, is cyclo [Tyr-D-Trp-Lys-Val-Phe ⁇ (4-(3- methoxyphenyl)imidazole)-Gly], cyclo [Trp-D-Trp-Lys-Val-Phe ⁇ (4-(3-methoxyphenyl)imidazole)-Gly], cyclo [Trp-D-Trp-Lys-Val-Phe ⁇ (4-(3-hydroxyphenyl)imidazole)-Gly], cyclo [Trp-D-Trp-Lys-Thr(OBzl)-Phe ⁇ (4-(3-methoxyphenyl)imidazole)-Gly], cyclo [Trp-D-Trp-Lys-Thr-Phe ⁇ (4-(3-hydroxyphenyl)imidazole)-Gly], cyclo [Trp-D-Tr
  • a preferred group of the group J compounds, designated group K, is cyclo [Trp-D-Trp-Lys-Thr-Phe ⁇ (4-(3-hydroxyphenyl)imidazole)-Gly], cyclo [Trp-D-Trp-Lys-Tyr(Bzl)-Phe ⁇ (4-(3-methoxyphenyl)imidazole-Gly], cyclo [Phe-D-Trp-Lys-Nal-Phe ⁇ (4-(3-hydroxyphenyl)imidazole-Gly], cyclo [Trp-D-Trp-Lys-Tyr(Bzl)-Phe ⁇ (4-(3-methoxyphenyl)imidazole-( ⁇ )Abu], cyclo [Trp-D-Trp-Lys-Tyr(Bzl)-Phe ⁇ (4-(4-methoxyphenyl)imidazole-Gly
  • a preferred group of the group K compounds, designated group L, is cyclo [Trp-D-Trp-Lys-Tyr(Bzl)-Phe ⁇ (4-(3-methoxyphenyl)imidazole-Gly], cyclo [Trp-D-Trp-Lys-Tyr(Bzl)-Phe ⁇ (4-(3-methoxyphenyl)imidazole-( ⁇ )Abu], cyclo [Trp-D-Trp-Lys-Tyr(Bzl)-Phe ⁇ (4-(4-methoxyphenyl)imidazole-Gly] and cycio [Trp-D-Trp-Lys-Tyr(Bzl)-Phe ⁇ (4-(phenyi)imidazole-Gly].
  • the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or formula
  • the present invention provides a method of eliciting a somatostatin receptor agonist effect in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof
  • the present invention provides a method of eliciting a somatostatin receptor antagonist effect in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound according of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof
  • the present invention provides a method of treating prolactin secreting adenomas restenosis, diabetes mellitus, hyperiipidemia, insulin insensitivity, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon, Nephropathy, gastric acid secretion, peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, irritable bowel syndrome, Dumping syndrome, watery diarrhea syndrome, AIDS related diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis, gastrointestinal hormone secreting tumors, cancer, hepatoma, angiogenesis, inflammatory disorders, arthritis, chronic allograft rejection, angioplasty, graft vessel bleeding or gastrointestinal bleeding, in a mammal in need thereof, which comprises administering to said mammal a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof
  • this invention provides a method of inhibiting the proliferation of helicobacter pylon in a mammal in need thereof, which comprises administering to said mammal a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof
  • this invention provides a process for preparing a compound of the formula
  • Prt is an amino acid side chain protecting group
  • the present invention provides, a process for preparing a compound of the formula
  • a compound of formula (a) for a compound of formula (a), forming an amide bond between the terminal amino group of the last amino acid defined by Y and the terminal carboxyl group of the last amino acid defined by Z by reacting a compound of the formula (a') with a peptide coupling reagent and an additive; or for a compound of formula (b), forming an amide bond between the terminal amino group, and the terminal carboxyl group of the last amino acid defined by Z by reacting a compound of the formula (b') with a peptide coupling reagent and an additive; or for a compound of formula (c), forming an amide bond between the terminal amino group of the last amino acid defined by Y and the terminal carboxyl group by reacting a compound of the formula (c') with a peptide coupling reagent and an additive; wherein, Prt is an amino acid side chain protecting group;
  • the present invention provides a process for preparing a compound of the formula
  • X' is halo; and all other variables are as defined for formula (I) shown hereinabove.
  • this invention provides a process for preparing a compound of the formula (I), which comprises coupling a compound of the
  • Y for each occurrence is independently a D- or L-naturai or unnatural ⁇ -amino acid optionally having a side chain with a protecting group;
  • Prt is an amine protecting group
  • R' is an alkyl ester or benzyl ester; n is 1 to 100; and all other variables are as defined for formula (I) shown hereinabove.
  • this invention provides a process for preparing a compound of formula (I), as defined hereinabove, which comprises coupling a compound of formula (B), activated as it's active ester, anhydride, or acid halide, with an N- deprotected peptide-resin (A 1 ), prepared by methods well known to those familiar with the peptide synthesis, deprotecting the N-terminal Fmoc group using piperidine in DMF, TAEA, or similar base and deprotecting and cleaving the resulting intermediate (B') from the resin using a strong acid. All variables are as defined for formula (I) shown hereinabove.
  • this invention provides, a process for preparing a compound of formula (I), which comprises coupling a compound of formula (B), activated as it's active ester, anhydride, or acid halide, with an N-deprotected peptide-resin (H), prepared by methods well known to those familiar with peptide synthesis, deprotecting the N-terminal Fmoc group using piperidine in DMF, TAEA, or similar base, acylating the liberated N-terminal amino group with an N ⁇ -Fmoc-protected amino acid (x) using peptide coupling reactions well known to those familiar with the art, repeating the base deprotection and coupling steps as required to incorporate additional amino acids (x), deprotecting and cleaving the resulting intermediate (C) from the resin using a strong acid. All variables are as defined for formula (I) shown hereinabove.
  • this invention provides, a process for preparing a compound of formula (I), which comprises coupling a compound of formula (B), activated as it's active ester, anhydride, or acid halide, to an amino-substituted resin, such as Tris- (alkoxy)-benzylam ⁇ ne resin (PAL Resin), 4-(2',4'-Dimethoxyphenyl-aminomethyl)- phenoxy Resin (N-deprotected Rink resin), or Benzhydrylamine resin, deprotecting the N-terminal terminal Fmoc group using piperidine in DMF, TAEA, or similar base, acylating the liberated N-terminal amino group with an N ⁇ -Fmoc-protected amino acid (x) using peptide coupling reactions well known to those familiar with the art, repeating the base deprotection and coupling steps as required to incorporate additional amino acids (x), deprotecting and cleaving the resulting intermediate (D') from the
  • this invention provides a process for preparing a compound of formula (I), which comprises reacting a compound of formula (B) with a base, such as Cs 2 C0 3 , reacting the resulting phenolic cesium salt (E') with a halomethylated polystyrene resin, such as Merrifield peptide resin, removing the Fmoc protecting group with piperidine or similar organic base, acylating the liberated N-terminal amino group with an N ⁇ -Fmoc-protected amino acid (x) using peptide coupling reactions well known to those familiar with the art, repeating the base deprotection and coupling steps as required to incorporate additional amino acids (x), deprotecting the final protected peptide sequence at the N-terminus with piperidine or similar organic base and at the C-terminus with Tfa, cyclizing the resulting intermediate (F') using peptide coupling reactions well known to those familiar with the art, and cleaving the resulting intermediate (G') from the
  • this invention provides a process for preparing a compound of formula (I), as defined hereinabove, which comprises coupling a compound of formula (B), activated as it's active ester, anhydride, or acid halide, with an N- deprotected peptide-resin (A'), prepared by methods well known to those familiar with the art, deprotecting the N-terminal Boc group using Tfa, and deprotecting side chain protecting groups and cleaving the resulting intermediate (H') from the resin using a strong acid such as HF. All variables are as defined for formula (I) shown hereinabove.
  • this invention provides a process for preparing a compound of formula (I), which comprises coupling a compound of formula (B), activated as it's active ester, anhydride, or acid halide, with an N-deprotected peptide-resin (H), prepared by methods well known to those familiar with the art, deprotecting the N-terminal Boc group using Tfa, acylating the liberated N-terminal amino group with an N ⁇ -Boc-protected amino acid (x) using peptide coupling reactions well known to those familiar with the art, repeating the Tfa deprotection and coupling steps as required to incorporate additional amino acids (x), deprotecting and cleaving the resulting intermediate (T) from the resin using a strong acid. All variables are as defined for formula (I) shown hereinabove.
  • this invention provides a process for preparing a compound of formula (I), which comprises reacting a compound of formula (B) with a base, such as Cs 2 C0 3 , reacting the resulting phenolic cesium salt (J') with a halomethylated polystyrene resin, such as Merrifield peptide resin, removing the Boc protecting group with Tfa, acylating the liberated N-terminal amino group with an N ⁇ -Boc- protected amino acid (x) using peptide coupling reactions well known to those familiar with the art, repeating the Tfa deprotection and coupling steps as required to incorporate additional amino acids (x), deprotecting the final protected peptide sequence at the N-terminus with Tfa and at the C-terminus with an inorganic base such as LiOH in aqueous DMF, cyclizing the resulting intermediate (K') with using peptide coupling reactions well known to those familiar with the art, and cleaving the resulting intermediate (L')
  • this invention provides a process for preparing a compound of formula (1 ), which comprises coupling a compound of formula (B), activated as it's active ester, anhydride, or acid halide, with an N-deprotected peptide, 4- Nitrobenzophenone oxime resin (M'), prepared by methods well known to those familiar with the art, deprotecting the N-terminal Boc group using Tfa, acylating the liberated N-terminal amino group with an N ⁇ -Boc-protected amino acid (x) using peptide coupling reactions well known to those familiar with the art, repeating the Tfa deprotection and coupling steps as required to incorporate additional amino acids (x), deprotecting the N-terminal Boc group with Tfa, cyclizing and cleaving the resulting intermediate N'-deprotected intermediate (N') by neutralizing with a suitable organic base, and removing side chain protecting groups with a strong acid, such as HF. All variables are as defined for formula (I)
  • heterocycle represents any heterocycie that may appear in the side chain of an ammo acid Examples include, but are not limited to, such heterocycles as benzothienyl, coumaryl, imidazolyl, indolyl, punnyl, py ⁇ dyl, py ⁇ midinyl, quinolmyl, thiazolyl, thienyl and tnazolyl
  • aryl as used herein, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic.
  • aryl groups include biphenyl, indanyl, naphthyl, phenyl, and 1 ,2,3,4-tetrahydronaphthalene
  • the affinity of a compound for human somatostatin subtype receptors 1 to 5 is determined by measuring the inhibition of [ 25 l-Tyr 11 ]SRIF-14 binding to CHO-K1 transfected cells.
  • the human sst, receptor gene was cloned as a genomic fragment.
  • a 1.5 Kb Pst ⁇ -Xmn ⁇ segment containing 100 bp of the 5'-untranslated region, 1.17 Kb of the entire coding region, and 230 bp of the 3'-untranslated region was modified by the Bg1 ll linker addition.
  • the resulting DNA fragment was subcloned into the BamH ⁇ site of a pCMV-81 to produce the mammalian expression plasmid (provided by Dr. Graeme Bell, Univ. Chicago).
  • a clonal cell line stably expressing the sst, receptor was obtained by transfection into CHO-K1 cells (ATCC) using the calcium phosphate co-precipitation method (1 ).
  • the plasmid pRSV-neo was included as a selectable marker.
  • Clonal cell lines were selected in RPMI 1640 media containing 0.5 mg/ml of G418 (Gibco), ring cloned, and expanded into culture.
  • the human sst 2 somatostatin receptor gene isolated as a 1.7Kb SamHI- Hind ⁇ genomic DNA fragment and subcloned into the plasmid vector pGEM3Z (Promega), was kindly provided by Dr. G. Bell (Univ. of Chicago).
  • the mammalian cell expression vector is constructed by inserting the 1.7Kb 6amH1-H/ ' ndll fragment into compatible restriction endonuclease sites in the plasmid pCMV5.
  • a clonal cell line is obtained by transfection into CHO-K1 cells using the calcium phosphate co- precipitation method.
  • the plasmid pRSV-neo is included as a selectable marker.
  • the human sst 3 was isolated at genomic fragment, and the complete coding sequence was contained within a 2.4 Kb SamHI/H/ndlll fragment.
  • the mammalian expression plasmid, pCMV-h3 was constructed by inserting the a 2.0 Kb A/col-H/ndlll fragment into the EcoR1 site of the pCMV vector after modification of the ends and addition of EcoR1 linkers.
  • a clonal cell line stably expressing the sst 3 receptor was obtained by transfection into CHO-K1 cells (ATCC) using the calcium phosphate co- precipitation method.
  • the plasmid pRSV-neo (ATCC) was included as a selectable marker. Clonal cell lines were selected in RPMI 1640 media containing 0.5 mg/ml of G418 (Gibco), ring cloned, and expanded into culture.
  • the human sst 4 receptor expression plasmid, pCMV-HX was provided by Dr. Graeme Bell (Univ. Chicago).
  • the vector contains the 1.4 Kb Nhe ⁇ -Nhe ⁇ genomic fragment encoding the human sst 4 , 456 bp of the 5'-untranslated region and 200 bp of the 3'-untranslated region, clone into the Xbal/£coR1 sites of PCMV-HX.
  • a clonal cell line stably expressing the sst 4 receptor was obtained by transfection into CHO- K1 cells (ATCC) using the calcium phosphate co-precipitation method.
  • the plasmid pRSV-neo was included as a selectable marker. Clonal cell lines were selected in RPMI 1640 media containing 0.5 mg/ml of G418 (Gibco), ring cloned, and expanded into culture.
  • the human sst 5 gene was obtained by PCR using a ⁇ genomic clone as a template, and kindly provided by Dr. Graeme Bell (Univ. Chicago).
  • the resulting 1.2 Kb PCR fragment contained 21 base pairs of the 5'-untranslated region, the full coding region, and 55 bp of the 3'-untranslated region.
  • the clone was inserted into EcoR1 site of the plasmid pBSSK(+).
  • the insert was recovered as a 1.2 Kb Hind ⁇ - Xba ⁇ fragment for subcloning into pCVM5 mammalian expression vector.
  • a clonal cell line stably expressing the SST 5 receptor was obtained by transfection into CHO- K1 cells (ATCC) using the calcium phosphate co-precipitation method.
  • the plasmid pRSV-neo was included as a selectable marker.
  • Clonal cell lines were selected in RPMI 1640 media containing 0.5 mg/ml of G418 (Gibco), ring cloned, and expanded into culture.
  • CHO-K1 cells stably expressing one of the human sst receptor are grown in RPMI 1640 containing 10% fetal calf serum and 0.4 mg/ml geneticin.
  • Cells are collected with 0.5 mM EDTA, and centrifuged at 500 g for about 5 min. at about 4°C.
  • the pellet is resuspended in 50 mM Tris, pH 7.4 and centrifuged twice at 500 g for about 5 min. at about 4°C.
  • the cells are lysed by sonication and centrifuged at 39000 g for about 10 min. at about 4°C.
  • the pellet is resuspended in the same buffer and centrifuged at 50000 g for about 10 min. at about 4°C and membranes in resulting pellet are stored at - 80°C.
  • Bound from free [ 125 l-Tyr 11 ]SRIF-14 is separated by immediate filtration through GF/C glass fiber filter plate (Unifilter, Packard) presoaked with 0.1 % polyethylenimine (P.E.I. ), using Filtermate 196 (Packard) cell harvester. Filters are washed with 50 mM HEPES at about 0-4°C for about 4 sec. and assayed for radioactivity using
  • Binding data are analyzed by computer-assisted nonlinear regression analysis (MDL) and inhibition constant (Ki) values are determined.
  • cAMP intracellular production CHO-K1 Cells expressing human somatostatin (SRIF-14) subtype receptors are seeded in 24-well tissue culture multidishes in RPMI 1640 media with 10% FCS and 0.4 mg/ml geneticin. The medium is changed the day before the experiment.
  • SRIF-14 human somatostatin
  • Cyclic AMP production is stimulated by the addition of 1mM forskolin (FSK) for about 15-30 minutes at about 37°C.
  • FSK forskolin
  • the agonist effect of a compound is measured by the simultaneous addition of FSK (1 ⁇ M) , SRIF-14 (10 "12 M to 10 ⁇ M) and a test compound (10 '10 M to 10 "5 M).
  • the antagonist effect of a compound is measured by the simultaneous addition of FSK (1 ⁇ M) , SRIF-14 (1 to 10 nM) and a test compound (10 "1 ° M to 10 '5 M).
  • reaction medium is removed and 200 ml 0.1 N HCI is added.
  • cAMP is measured using radioimmunoassay method (Kit FlashPlate SMP001A, New England Nuclear). Radioligand Binding Assay
  • Membranes for in vitro receptor binding assays were obtained by homogenizing (Polytron, setting 6, 15 sec) the CHO-K1 cells, expressing the hsst receptor subtypes, in ice-cold 50 mM Tris-HCI and centrifuging twice at 39,000 g (10 min), with an intermediate resuspension in fresh buffer. The final pellets were resuspended in 10 mM Tris-HCI for assay.
  • hsstl hsst3, hsst4, hsst ⁇ assays
  • aliquots of the membrane preparations were incubated (for about 30 min at about 37 °C with 0.05 nM [125l-Tyr11JSRIF-14 in 50 mM HEPES (pH 7.4) containing BSA (10 mg/ml); MgCI2 (5 mM)), Trasylol (200 KlU/ml), bacitracin (0.02 mg/ml), and phenylmethylsulphonyl fluoride (0.02 mg/ml).
  • the final assay volume was 0.3 ml.
  • [125l]MK-678 (0.05 nM) was employed as the radioligand and the incubation time was about 90 min at about 25 °C.
  • the incubations were terminated by rapid filtration through GF/C filters (pre-soaked in 0.3% polyethylenimine) using a Brandel filtration manifold. Each tube and filter were then washed three times with 5-ml aliquots of ice-cold buffer.
  • Specific binding was defined as the total radioligand bound minus that bound in the presence of 1000 nM SRIF-14(hsst1 ,3,4,5), or 1000 nM MK-678 for hsst2.
  • the compounds of the instant invention can be in vivo assayed for the uses associated with binding to the somatostatin receptor, including specificity binding to the somatostatin subtype receptor(s), according to methods well known to those skilled in the art as exemplified by the following references: I. Shimon, et. al., "Somatostatin receptor subtype specificity in human fetal pituitary cultures", J. Gin. Invest., Vol. 99, No.4, pp. 789-798, 1997; and C. Gilon, et. al., "A backbone-cyclic, receptor 5-selective somatostatin analogue: Synthesis, bioactivity, and nuclear magnetic resonance conformational analysis", J. Med. Chem. 1998, 41 , 919-929.
  • Somatostatin agonists can be used to suppress growth hormone and more particularly GH secreting adenomas (acromegaly) and TSH secreting adenomas; treat prolactin secreting adenomas; inhibit insulin and/or glucagon and more particularly diabetes mellitus, angiopathy, proliferative retinopathy, dawn phenomenon and nephropathy; inhibition of gastric acid secretion and more particularly peptic ulcers; enterocutaneous and pancreaticocutaneous fistula; irritable bowel syndrome; Dumping syndrome; watery diarrhea syndrome; AIDS related diarrhea; chemotherapy-induced diarrhea; acute or chronic pancreatitis and gastrointestinal hormone secreting tumors; treatment of cancer such as hepatoma; inhibition of angiogenesis; treatment of inflammatory disorders such as arthritis; retinopathy; chronic allograft rejection; angioplasty; preventing graft vessel and gastrointestinal bleeding.
  • GH secreting adenomas acromegaly
  • compositions comprising, as an active ingredient, at least one of the compounds of the instant invention as described herein in association with a pharmaceutically acceptable carrier.
  • a compound of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant
  • nasal, vaginal, rectal, sublingual or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch.
  • Such dosage forms can also comprise, as is normal practice, additional substances other than such inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents. Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • non-aqueous solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
  • Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as coca butter or a suppository wax.
  • compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
  • a compound of this invention can be administered in a sustained release composition such as those described in the following patents.
  • U.S. Patent No. 5,672,659 teaches sustained release compositions comprising a bioactive agent and a polyester.
  • U.S. Patent No. 5,595,760 teaches sustained release compositions comprising a bioactive agent in a gelable form.
  • U.S. Application No. 08/929,363 filed September 9, 1997, teaches polymeric sustained release compositions comprising a bioactive agent and chitosan.
  • U.S. Application No. 08/740,778 filed November 1 , 1996 teaches sustained release compositions comprising a bioactive agent and cyclodextrin.
  • the dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained.
  • the selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. Generally, dosage levels of between 0.0001 to 100 mg/kg of body weight daily are administered to humans and other animals, e.g., mammals, to obtain a therapeutic effect.
  • a preferred dosage range is 0.01 to 5.0 mg/kg of body weight daily which can be administered as a single dose or divided into multiple doses.
  • a compound of this invention can be synthesized according to the following description and Scheme I.
  • an amino acid, protected on the ⁇ -amino group with Boc, Cbz or other suitable group is converted to a carboxylate salt with an inorganic base, for example NaOH, KOH, K 2 C0 3 , or most preferably Cs 2 C0 3 , in a polar solvent such as H 2 0, DMF, THF, or the like.
  • a polar aprotic solvent such as DMF and a suitable ⁇ -halo ketone is added with stirring at about -20°C to about 100°C, most preferably at room temperature.
  • intermediate (A) is deprotected using catalytic hydrogenation or strong acids such as HF, HCI, HBr or Tfa.
  • the ⁇ -nitrogen may then be protected with a base sensitive protecting group such as the Fmoc group using commercially available N-(9-fluorenylmethoxycarbonyloxy)succinimide and K 2 C0 3 in, for example, acetonitrile and water.
  • intermediate B, B', or B" is used as an anchor group for the continuous solution phase synthesis of a target peptide.
  • the anchor group is dissolved in ethyl acetate at a concentration of about 50-200 mmol per liter and about 1 to 5 molar equivalents or, more preferably, 1.1 to 1.5 molar equivalents of an N ⁇ -Fmoc protected amino acid, in the form of its activated ester, anhydride or acid halide is added.
  • the mixture is stirred over a second layer of weak base such as aqueous Na 2 C0 3 or, more preferably, aqueous NaHC0 3 solution until the reaction is complete.
  • the aqueous layer is removed and about 1 to 10 ml/mmol or, more preferably, about 2-4 ml/mmol of TAEA or piperidine is added and the mixture is stirred for about 30 minutes.
  • the final amino acid may be protected on N ⁇ with a Boc or an Fmoc group.
  • the N-terminai and C-terminal protecting groups are removed with aqueous base or with strong acids, and the resulting peptide intermediate may be cyclized using classical peptide coupling techniques as described in "The Practice of Peptide Synthesis", Bodanszky and Bodanszky, Springer-Varlag, 1984. Accordingly, the peptide intermediate is dissolved in an aprotic solvent such as DMF and the solution is made basic by addition of tertiary amine base such as 4-methyl- morpholine.
  • the carboxylate portion of the intermediate is activated by addition of a 1- to 6-fold molar excess of a carbodiimide, such as DCC or EDC, and an additive such as, for example, 1 -hydroxy benzotriazole.
  • a carbodiimide such as DCC or EDC
  • an additive such as, for example, 1 -hydroxy benzotriazole.
  • the mixture is stirred at about 0° to 100°C, most preferably at about room temperature, until the reaction is complete.
  • the protected peptide is freed of protecting groups using catalytic hydrogenation or strong acids such as HF, HCI, HBr or Tfa to yield final product (C), where R 1 to R 5 , a, b, Y, Z, and n are as defined above for formula (I).
  • the infusion mass spectral data was measured on a Finnigan SSQ 7000 spectrometer equipped with an ESI (electrospray ionization) source.
  • NMR data was obtained on a 300MHz Varian Unity spectrometer from samples at concentrations of about 10-20mg/ml in the designated solvents.
  • compounds of the present invention can be prepared using solid phase peptide synthesis techniques.
  • Intermediate D is then converted to it's cesium salt by the action of cesium carbonate.
  • the cesium salt is reacted, in excess, with Merrifield resin to provide intermediate E.
  • Intermediate E is subject to elaboration using standard Boc solid phase peptide synthesis or standard Fmoc solid phase synthesis as previously described to yield intermediate F.
  • the C-terminal ethyl ester is unmasked using a suitable base, for example, LiOH in aqueous DMF and the peptide is cyclized using standard activation protocol, for example, a carbodiimide with, for example, hydroxy benzotriazole and a tertiary amine base, for example, diisopropylethyl amine to provide intermediate G.
  • a suitable base for example, LiOH in aqueous DMF
  • standard activation protocol for example, a carbodiimide with, for example, hydroxy benzotriazole and a tertiary amine base, for example, diisopropylethyl amine
  • Example 1 was synthesized according to synthetic scheme 1 as shown below:
  • Example 1 was synthesized according to synthetic scheme 1 as shown below:
  • Step b 2-(1-(S)-((Fluorenylmethoxy)carbonyl)amino-2-phenylethyl)-4-(3-methoxy- phenyl)-imidazoie
  • Step c 2-(1-(S)-((Fluorenylmethoxy)carbonyl)amino-2-phenylethyl)-4-(3-methoxy- phenyl)-1-triphenylmethyl-imidazole Intermediate 1b (13.9g, 26.9mmol) was dissolved in CH 2 CI 2 (50ml) under N 2 ,
  • Step d 2-(1-(S)-((Fmoc-Tyr(OBzl)-D-Trp-Lys(Cbz)-Val)amino-2-phenylethyl)-4-(3- methoxyphenyl)-1-(triphenylmethyl)-imidazole
  • the intermediate was then sequentially deprotected and coupled with Fr ⁇ oc- Lys(Cbz)-OSu, Fmoc-D-Trp-OSu and Fmoc-Tyr(OBzl)-OSu in a manner similar to the Fmoc-Val-F cycle described immediately above.
  • the EtOAc layer was diluted with 1.5 volumes of hexanes and applied to a silica gel column for purification by flash chromatography using 50:30:20/CH 2 CI 2 :EtOAc:hexanes first and then with 4:1/ EtOAc:hexanes as eluants. Product fractions were pooled and concentrated under vacuum to yield intermediate 1d as a white foam, 1.90g, (46%). Mass spec 1581.2 MNa+, 1559.5 MH+.
  • Step e 1 -((2-Ethoxy-2-oxo)ethyl)-2-(1 -(S)-((Fmoc-Tyr(OBzl)-D-Trp-Lys(Cbz)- Val)amino-2-phenylethyl)-4-(3-methoxyphenyl)-imidazole
  • Intermediate 1d (519mg, 0.33mmol) was dissolved in Tfa (10ml) containing iPr 3 SiH (205ul, I .Ommol) and the mixture was stirred for about 15 minutes. Intermediate was precipitated by addition of ethyl ether (60mi) and filtered off. Mass spec 1316 MH+.
  • Example 2 cyclo [Tyr(OBzl)-D-Trp-Lys-Val-Phe ⁇ (4-(3-methoxyphenyl)imidazole)-Gly]
  • Example 2 was prepared substantially according to synthetic scheme 1 , Example 1 , but using the appropriate amino acids. Pure fractions of the less polar peak from the purification of 1 g were combined, concentrated, and lyophilized (2X10ml 0.5% HCI, then 1 X10ml H 2 0) to yield the title product of Example 2, 33mg (21 %). Mass spec. 1000.4 MH+.
  • Example 3 was prepared according to synthetic scheme 1 in a manner substantially similar to Example 1 but with the following differences: Step d: 2-(1-(S)-((Fmoc-Trp-D-Trp-Lys(Cbz)-Val-)amino-2-phenylethyl)-4-(3- methoxyphenyl)-1-(triphenylmethyl)-imidazole Intermediate 1c (757mg, I .Ommol) was dissolved in EtOAc (20ml), tris(2- aminoethyl)amine (3ml) was added and the mixture stirred vigorously for about Vz hour.
  • the EtOAc layer was washed with saturated NaCI solution (2 X 60ml) and then with 10% phosphate buffer solution adjusted to a pH of about 5.5 (3 X 20ml).
  • the EtOAc layer was stirred over saturated NaHC0 3 solution (20ml) and Fmoc-Val-F (825mg, 2.33mmol) was added. The reaction was stirred for about 1 hour and the aqueous layer was removed.
  • the intermediate was sequentially deprotected and coupled with Fmoc- Lys(Cbz)-OSu, Fmoc-D-Trp-OSu and Fmoc-Trp-OSu in a manner similar to the Fmoc-Val-F cycle described immediately above.
  • the EtOAc layer was diluted with 1.5 volumes of hexanes and applied to a silica gel column for purification by flash chromatography using 50:30:20/CH 2 CI 2 :EtOAc:hexanes first and then with 4:1/ EtOAc:hexanes as eluants. Product fractions were pooled and concentrated under vacuum to yield intermediate 3d as a white foam, 1.02g, (68%).
  • Step g cyclo [Trp-D-Trp-Lys-Val-Phe ⁇ (4-(3-methoxyphenyl)imidazole)-Gly]
  • Example 4 was prepared according to synthetic scheme 1 in a manner substantially similar to that of Example 1 with the following differences:
  • Step g cyclo [Trp-D-Trp-Lys-Val-Phe ⁇ (4-(3-hydroxyphenyl)imidazole)-Gly]
  • Intermediate 3f (150mg, 0.14mmol) was dissolved in CH 2 CI 2 (12ml) and a solution of 1M BBr3 in hexanes was added under N 2 . The resulting slurry was stirred for about 1 / 2 hour. Methanol (10ml) was added and the mixture was concentrated under vacuum. The crude mixture was purified by preparative HPLC on a C 18 column using a gradient of 24% to 48% CH 3 CN/ 0.2 % NH 4 OAc over about 50 minutes. Pure fractions were combined, concentrated, and lyophilized (2X10ml H 2 0) to yield the title compound of Example 4, 40mg (29%). Mass spec. 919.4 MH+.
  • Example 5 was prepared according to scheme 1 in a manner substantially similar to Example 3 except that Fmoc-Thr(OBzl)-F was used in place of Fmoc-Val-F in step d. Mass spec 1025.5 MH+.
  • Example 6 was prepared according to scheme 1 in a manner substantially analogous to Example 4 except that intermediate 5f, cyclo[Trp-D-Trp-Lys(Cbz)-
  • Example 7 was prepared according to scheme 1 in a manner substantially analogous to Example 3 except that Fmoc-Abu-F was used in place of Fmoc-Val-F in step 3d and cyclization with carbodiimide and HOBt was not performed in step 3f. Mass spec 937.3 MH+.
  • Example 8 was prepared according to scheme 1 in a manner substantially analogous to Example 3 except that Fmoc-Abu-F was used in place of Fmoc-Val-F in step 3d. Mass spec 919.5 MH+.
  • Example 9 was prepared according to Scheme 2.
  • Step a 2-(1-(S)-amino-2-phenylethyl)-4-(1 ,1-dimethylethyl)-imidazole
  • Boc-(L)-Phenylalanine (5.31 g, 20.0mmol) and Cs 2 C0 3 (3.26g, lO.Ommol) were combined in 1:1/DMF:H 2 0 (50 ml) and the mixture was swirled until a homogeneous mixture was obtained. Solvents were removed under reduced pressure and the residue was dissolved in DMF (50ml) and 1-chioropinacolone (2.63ml, 20.0mmol) was added. The mixture was stirred overnight at room temperature then concentrated under reduced pressure. The resulting keto-ester was dissolved in xylenes (100ml) and the CsBr was filtered off. Ammonium acetate (25.
  • Step h 2-(1-(S)-((Fmoc-Phe-D-Trp-Lys(Boc)-Tyr(OBzl))-amino-2-phenylethyl)-4- (1 ,1-dimethylethyl)-1 H-imidazole
  • the intermediate was sequentially deprotected and coupled with Fmoc- Lys(Cbz)-OSu, Fmoc-D-Trp-OSu and Fmoc-Phe-OSu in a manner similar to the Fmoc-Tyr(OBzl)-OSu cycle described immediately above.
  • the EtOAc layer was applied to a silica gel column for purification by flash chromatography using 1% acetic acid/EtOAc as eluant. Product fractions were pooled and concentrated under vacuum. The crude product was redissolved in EtOAc, precipitated by addition of hexanes and filtered off. The solid was dried under vacuum to yield intermediate 9h, 1.67g, (52%). Mass spec 1280.7 MH+.
  • Step e 4-(1 ,1-dimethylethyl)-2-(1-(S)-((Fmoc-Phe-D-Trp-Lys(Boc)-Tyr(OBzl)- )amino-2-phenylethyl)-1-(2-ethoxy-2-oxo-ethyl)-imidazole
  • Step g cyclo [Phe-D-Trp-Lys-Tyr-Phe ⁇ (4-(1 ,1-dimethylethyl)imidazole)-Gly]
  • Intermediate 9f (crude, 0.085mmol) was dissolved in Tfa
  • Example 10 was prepared according to scheme 1 in a manner analogous to Example 3 except that Fmoc-Phe-OSu was used in place of Fmoc-Trp-F in step d. Mass spec. 894.4 MH+
  • Example 1 1 was prepared according to scheme 1 in a manner analogous to Example 3 except that Fmoc-Phe-OH was used in place of Fmoc-Trp-F and Fmoc- Tyr(OBzl)-OH was used in place of Fmoc-Val-F in step d.
  • the Fmoc-Tyr(OBzl)-OH was activated with DCC and commercially available HOAt.
  • the crude mixture in step g was composed of completely deprotected material (both Cbz and benzyl ether removed) and partially deprotected material (Cbz removed and benzyl ether intact). The less polar peak resulting from partial deprotection yielded the title compound of Example 11. Mass spec 1048.5 MH+.
  • Example 12 was prepared according to scheme 1 in a manner analogous to Example 3 except that Fmoc-Phe-OH was used in place of Fmoc-Trp-F and Fmoc- Tyr(OBzl)-OH was used in place of Fmoc-Val-F in step d.
  • the Fmoc-Tyr(OBzl)-OH was activated with DCC and commercially available HOAt.
  • the crude mixture in step g was composed of completely deprotected material (both Cbz and benzyl ether removed) and partially deprotected material (Cbz removed and benzyl ether intact). The more polar peak resulting from complete deprotection yielded the title compound of Example 12. Mass spec 958.4 MH+.
  • Example 13 cyclo [Phe-D-Trp-Lys-Tyr-Phe ⁇ (4-(3-hydroxyphenyl)imidazoie-Gly]
  • Example 13 was prepared according to scheme 1 in a manner analogous to
  • Example14 was prepared according to Scheme 2 in a manner substantially analogous to Example 9 with the following differences:
  • Step h 2-(1-(S)-((Fmoc-Trp-D-Trp-Lys(Cbz)-Tyr(Bzl))-amino)-2-phenylethyl)-4-(3- methoxyphenyl)-1-(triphenylmethyl)-imidazole Peptide synthesis was performed in a manner analogous to step 9h except Fmoc-
  • Trp-OSu was used in place of Fmoc-Phe-OSu
  • Fmoc-Lys(Boc)-OSu was used in place of Fmoc-Lys(Cbz)-OSu
  • Fmoc-Tyr(Bzl)-OSu was used in place of Fr ⁇ oc-
  • Step e 1 -((2-Ethoxy-2-oxo)ethyl)-2-(1-(S)-((Fmoc-Trp-D-Trp-Lys(Boc)- Tyr(OBzl))- amino)-2-phenylethyl)-4-(3-methoxyphenyi)-imidazole
  • Step f cyclo [Trp-D-Trp-Lys(Boc)-Tyr(Bzl)-Phe ⁇ (4-(3-Methoxyphenyl)imidazole)-
  • Step g cyclo [Trp-D-Trp-Lys-Tyr(Bzl)-Phe ⁇ (4-(3-methoxyphenyl)imidazoie)-Gly]
  • Intermediate 14f (240mg, 0.20mmol) was dissolved in CH 2 CI 2 (10mt) and Tfa
  • Example 15 was prepared according to synthetic scheme 1 in a manner substantially analogous to Example 4 with the following exception: Step g: cyclo [Tyr-D-Trp-Lys-Val-Phe ⁇ (4-(3-hydroxyphenyl)imidazole)-Gly]
  • Example 16 cyclo [Phe-D-Trp-Lys-Nal-Phe ⁇ (4-(3-hydroxyphenyl)imidazole-Gly]
  • Example 16 was prepared according to scheme 1 in a manner substantially analogous to Example 3 with the following differences:
  • Step d 2-(1-(S)-((Fmoc-Phe-D-Trp-Lys(Cbz)-Nal-)amino)-2-phenylethyl)-4-(3- methoxyphenyl)-1-(triphenylmethyl)-imidazole
  • Intermediate 16d was prepared in a manner substantially similar to intermediate 1d except that Fmoc-Nal-OAt was used in place of Fmoc-Val-F and
  • Fmoc-Phe-OH was used in place of Fmoc-Tyr(Bzl)-OH.
  • Step g cyclo [Tyr-D-Trp-Lys-Val-Phe ⁇ (4-(3-hydroxyphenyl) ⁇ m ⁇ dazole)-Gly] Step 16g was carried out in a manner substantially analogous to step 4g to yield the title compound of Example 16.
  • Example 17 was prepared according to scheme 1 in a manner substantially analogous to Example 16 with the following exceptions:
  • Example 18 was prepared according to synthetic scheme 3.
  • Step i 2-(1-(S)-((Phenylmethoxy)carbonyl)-am ⁇ no-2-phenylethyl)-4-(4- methoxyphenyl)- ⁇ m ⁇ dazo!e
  • Step k 2-(1-(S)-((Boc-Trp-D-Trp-Lys(Cbz)-Val)-amino-2-phenylethyl)-1-((4-(1 ,1- dimethylethoxy)-4-oxo)butyl)-4-(3-methoxyphenyl)-imidazole
  • Step f cyclo [Trp-D-Trp-Lys(Cbz)-Tyr(Bzl)-Phe ⁇ (4-(3-methoxyphenyl)imidazoie- ( ⁇ )Abu]
  • Example 19 was prepared according to Scheme 3 in a manner substantially similar to Example 18 with the following differences: Step j: 2-(1-(S)-amino-2-phenylethyl)-1-(2-(1 ,1 -dimethylethoxy)-2-oxo-ethyl)-4-(4- methoxypheny -imidazole
  • Step g Catalytic hydrogenation and work-up performed in a manner substantially analogous to step 18g yielded the title product (22mg, 4%) as a white solid. Mass spec. 1088.2 MH+.
  • Example 20 cyclo [Trp-D-Trp-Lys-Tyr(Bzl)-Phe ⁇ (4-(phenyl)imidazole-Gly]
  • Example 20 was prepared according to Scheme 3 in a manner substantially analogous to Example 18 except that 2-bromoacetophenone was used in place of 2- bromo-3'-methoxyacetophenone in step i.
  • Example 21 cyclo [Trp-D-Trp-Lys-Tyr(Bzl)-Phe ⁇ (4-(3-methoxyphenyl)imidazole-( ⁇ )Ahx]
  • Example 21 was prepared according to Scheme 3 in a manner substantially analogous to Example 18 with the following differences: Step j: 2-(1-(S)-Amino-2-phenylethyl)-1-(6-(ethoxy)-6-oxo-hexyl)-4-(3- methoxyphenyl)-imidazole
  • Step k and step I 2-(1-(S)-((H-Trp-D-Trp-Lys(Boc)-Tyr(OBzl)- 2-(1-(S)-amino-2- phenylethyl)-1-(6-(ethoxy)-6-oxo-hexyl)-4-(3-methoxyphenyl)-imidazole
  • Fmoc-Tyr(OBzl)-OAt was prepared by mixing Fmoc-Tyr(OBzl)-OH (493mg, 1.00 mmol), HOAt (136mg, I .Ommol) and DCC (206mg, I .Ommol) in 8 ml EtOAc for about / 2 hour then filtering off the dicyclohexylurea. The resulting solution was added to a solution of intermediate 21 j (457mg, 0.9mmole) in EtOAc (4ml) and the mixture was stirred over saturated NaHC0 3 solution (10mi) until the reaction was complete by mass spectral analysis.
  • the intermediate was sequentially deprotected and coupled with Fmoc- Lys(Cbz)-OSu, Fmoc-D-Trp-OSu and Fmoc-Trp-OSu in a manner substantially similar to the Fmoc-Tyr(OBzl)-OAt cycle described immediately above.
  • a final Fmoc deprotection yielded the N-terminally deprotected intermediate ethyl ester.
  • the EtOAc layer was dried over Na 2 S0 4 , filtered and diluted with 4 volumes of hexanes. Solvents were poured off and the residue was triturated with hexanes to yield product as a solid (0.67g, 58%) which was used without further purification.
  • Example 18 to yield the title compound of Example 21 as a white powder, 62mg. Mass spec. 1143.9 MH+
  • Example 22 cyclo [Trp-D-Trp-Lys-Tyr(Bzl)-Phe ⁇ (4-(3-hydroxyphenyl)imidazole-( ⁇ )Abu]
  • Example 22 was prepared according to Scheme 3 in a manner substantially analogous to Example 18 with the following differences: step j: 2-(1-(S)-Amino-2-phenylethyl)-1-(4-(ethoxy)-4-oxo-butyl)-4-(4-hydroxyphenyl)- imidazole

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Abstract

Cette invention se rapporte à des dérivés cycliques contenant un imitateur de liaison cis-amide d'imidazole, qui se fixent sélectivement à des sous-types de récepteurs de somatostatine, ainsi qu'à leur utilisation thérapeutique contre des états pathologiques que l'on peut traiter en déclenchant un effet agoniste ou antagoniste à partir des récepteurs de somatostatine de ces sous-types. Cette invention se rapporte également à des procédés servant à fabriquer ces composés.
PCT/US1999/013304 1998-06-16 1999-06-11 Analogues de somatostatine cycliques WO1999065942A1 (fr)

Priority Applications (8)

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US09/719,784 US6602849B1 (en) 1998-06-16 1999-06-11 Cyclic somatostatin analogs
JP2000554767A JP2002518409A (ja) 1998-06-16 1999-06-11 サイクリックソマトスタチン類似体
CA002335184A CA2335184A1 (fr) 1998-06-16 1999-06-11 Analogues de somatostatine cycliques
HU0102902A HUP0102902A3 (en) 1998-06-16 1999-06-11 Cyclic somatostatin analogs, process for production thereof and their use
EP99931793A EP1086131A1 (fr) 1998-06-16 1999-06-11 Analogues de somatostatine cycliques
PL99345037A PL345037A1 (en) 1998-06-16 1999-06-11 Cyclic somatostatin analogs
AU48223/99A AU745493B2 (en) 1998-06-16 1999-06-11 Cyclic somatostatin analogs
NO20006320A NO20006320L (no) 1998-06-16 2000-12-12 Cykliske somatostatin-analoger

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WO2002010140A3 (fr) * 2000-08-01 2002-08-08 Sod Conseils Rech Applic Dérivés imidazolyles
WO2001009090A3 (fr) * 1999-07-30 2002-08-08 Sod Conseils Rech Applic Derives d'hydantoines, de thiohydantoines, de pyrimidinediones et de thioxopyrimidinoneses, leurs procedes de preparation et leur application a titre de medicaments
WO2004071448A3 (fr) * 2003-02-12 2004-10-14 Transtech Pharma Inc Derives d'azole substitues comme agents therapeutiques
WO2006063465A1 (fr) * 2004-12-15 2006-06-22 Diamedica Inc. Traitement de resistance a l'insuline par modulation de somatostatine au moyen d'antagonistes du recepteur de la somatostatine
WO2007070826A1 (fr) * 2005-12-14 2007-06-21 Bristol-Myers Squibb Company Analogues de l'arylpropionamide, de l'arylacrylamide, de l'arylpropynamide ou de l'arylmethyluree en tant qu'inhibiteurs du facteur xia
US7238695B2 (en) 1998-06-12 2007-07-03 Societe De Conseils De Recherches Et D'applications Scientifiques, Sas Imidazolyl derivatives
EP2351743A4 (fr) * 2008-10-27 2012-05-09 Takeda Pharmaceutical Composé bicyclique
US9121025B2 (en) 2008-09-26 2015-09-01 Ambrx, Inc. Non-natural amino acid replication-dependent microorganisms and vaccines
US9382306B2 (en) 2008-09-30 2016-07-05 Ipsen Pharma S.A.S. Octapeptide compounds derived from somatostatin and the therapeutic use thereof

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ES2365815T3 (es) * 2005-12-14 2011-10-11 Bristol-Myers Squibb Company Análogos de arilpropionamida, arilacrilamida, arilpropinamida o arilmetilurea como inhibidores del factor xia.
MX2018009655A (es) 2016-02-09 2019-05-22 Cdrd Ventures Inc Compuestos antagonistas receptores de somatostatina y métodos para utilizarlos.

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WO1998004583A1 (fr) * 1996-07-31 1998-02-05 Peptor Ltd. Analogues de la somatostatine cyclises par squelette a contrainte de conformation

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WO1997030053A1 (fr) * 1996-02-16 1997-08-21 Biomeasure Incorporated Inhibiteurs de la farnesyl-transferase
WO1998004583A1 (fr) * 1996-07-31 1998-02-05 Peptor Ltd. Analogues de la somatostatine cyclises par squelette a contrainte de conformation

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SHIMON L ET AL: "SOMATOSTATIN RECEPTOR SUBTYPE SPECIFICITY IN HUMAN FETAL PITUITARY CULTURES", JOURNAL OF CLINICAL INVESTIGATION, vol. 99, no. 4, 15 February 1997 (1997-02-15), pages 789 - 798, XP002073099, ISSN: 0021-9738 *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7238695B2 (en) 1998-06-12 2007-07-03 Societe De Conseils De Recherches Et D'applications Scientifiques, Sas Imidazolyl derivatives
WO2001009090A3 (fr) * 1999-07-30 2002-08-08 Sod Conseils Rech Applic Derives d'hydantoines, de thiohydantoines, de pyrimidinediones et de thioxopyrimidinoneses, leurs procedes de preparation et leur application a titre de medicaments
US6759415B1 (en) 1999-07-30 2004-07-06 Societe De Conseils De Recherches Et D' Applications Scientifiques Hydantoin thiohydantoin pyrimidinedione and thioxopyrimidinone derivatives preparation method and use as medicines
US7566734B2 (en) 2000-08-01 2009-07-28 Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. Imidazolyl derivatives
AU2001279098B2 (en) * 2000-08-01 2005-04-14 Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S Imidazolyl derivatives
US7638546B1 (en) 2000-08-01 2009-12-29 Ipsen Pharma S.A.S. Imidazolyl derivatives
WO2002010140A3 (fr) * 2000-08-01 2002-08-08 Sod Conseils Rech Applic Dérivés imidazolyles
WO2004071448A3 (fr) * 2003-02-12 2004-10-14 Transtech Pharma Inc Derives d'azole substitues comme agents therapeutiques
WO2006063465A1 (fr) * 2004-12-15 2006-06-22 Diamedica Inc. Traitement de resistance a l'insuline par modulation de somatostatine au moyen d'antagonistes du recepteur de la somatostatine
US8017575B2 (en) 2004-12-15 2011-09-13 Wilfred Wayne Lautt Treatment of insulin resistance by modulating somatostatin using somatostatin receptor antagonists
WO2007070826A1 (fr) * 2005-12-14 2007-06-21 Bristol-Myers Squibb Company Analogues de l'arylpropionamide, de l'arylacrylamide, de l'arylpropynamide ou de l'arylmethyluree en tant qu'inhibiteurs du facteur xia
US7626039B2 (en) 2005-12-14 2009-12-01 Bristol-Myers Squibb Company Arylpropionamide, arylacrylamide, ayrlpropynamide, or arylmethylurea analogs as factor XIa inhibitors
EA014245B1 (ru) * 2005-12-14 2010-10-29 Бристол-Маерс Сквибб Компани Аналоги арилпропионамида, арилакриламида, арилпропинамида или арилметилмочевины в качестве ингибиторов фактора xia
US8252830B2 (en) 2005-12-14 2012-08-28 Bristol-Myers Squibb Company Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor XIa inhibitors
US8604056B2 (en) 2005-12-14 2013-12-10 Bristol-Myers Squibb Company Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor XIa inhibitors
US9121025B2 (en) 2008-09-26 2015-09-01 Ambrx, Inc. Non-natural amino acid replication-dependent microorganisms and vaccines
US9382306B2 (en) 2008-09-30 2016-07-05 Ipsen Pharma S.A.S. Octapeptide compounds derived from somatostatin and the therapeutic use thereof
EP2351743A4 (fr) * 2008-10-27 2012-05-09 Takeda Pharmaceutical Composé bicyclique
US8501804B2 (en) 2008-10-27 2013-08-06 Takeda Pharmaceutical Company Limited Bicyclic compound

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AR021161A1 (es) 2002-07-03
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AU4822399A (en) 2000-01-05
CN1200000C (zh) 2005-05-04
AU745493B2 (en) 2002-03-21
EP1086131A1 (fr) 2001-03-28
HUP0102902A2 (hu) 2002-01-28
NO20006320L (no) 2001-02-12
CA2335184A1 (fr) 1999-12-23
CN1305496A (zh) 2001-07-25
HUP0102902A3 (en) 2002-02-28

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